Lung cancer is one of the most prevalent malignant neoplasms and represents the leading cause of cancer-related mortality globally (Bray et al., 2018, Huang and Zhang, 2023). While surgery is the optimal therapeutic option, chemotherapy remains the primary treatment for advanced lung cancer patients (Gandhi et al., 2018). Among the current chemotherapeutic drugs, paclitaxel is widely used as a first-line chemotherapeutic agent for lung and other cancers (Majem et al., 2019, Ramalingam and Belani, 2004). It affects cell mitosis (Weaver, 2014), inhibits cell growth (Weaver, 2014),and is effective against a range of advanced malignancies (Razi et al., 2015; Huang et al., 2017; Khanna et al., 2015; Gligorov and Lotz, 2004). However, the development of acquired drug resistance often results in disease progression or recurrence within a short time, significantly limiting the drug's clinical efficacy (Lario et al., 2007). It is therefore of great significance to explore the underlying mechanism of paclitaxel resistance in order to reverse this phenomenon and improve the prognosis of patients.

Previous studies have identified several mechanisms underlying paclitaxel resistance in cancer. P-glycoprotein (P-gp), also known as Multidrug Resistance Protein 1 (MDR1), is encoded by the ABCB1 gene and is a well-established mediator of paclitaxel resistance (Januchowski et al., 2014). Overexpression of P-gp has been demonstrated to result in increased drug efflux, thereby reducing the efficacy of chemotherapeutic drugs in killing tumor cells (Distefano et al., 1998; Gottesman et al., 2002). Additionally, evidence suggests that paclitaxel resistance can also arise from β-tubulin mutations, which reduce the drug’s affinity for tubulin (Huzil et al., 2007, Yin et al., 2013). Moreover, up-regulation of the antiapoptotic Bcl-2 family members, such as Bcl-2 and Bcl-XL, or down-regulation of the proapoptotic Bax in apoptosis pathways has been reported linked to paclitaxel resistance (Tabuchi et al., 2009, Wang et al., 2000). However, the underlying mechanisms of acquired paclitaxel resistance in lung cancer, particularly the proteins that are downregulated in paclitaxel resistance, remain largely unclear.

In this study, we developed several lung cancer cell lines with varying levels of acquired paclitaxel resistance and performed transcriptomic RNA sequencing to identify genes differentially expressed in drug-resistant cells. We observed that, unlike the stepwise upregulation of known paclitaxel resistance inducers (ABCB1, TMEM243, and ID1), alpha-2-macroglobulin (α2 M), encoded by the A2M gene, was progressively downregulated as paclitaxel resistance developed.

A2M is a large tetrameric secreted protein (molecular weight 725,000) found in mammalian blood, composed of identical subunits (Cater et al., 2019, Raymond et al., 2009). Initially identified as a plasma proteinase inhibitor and cytokine transporter with broad specificity, A2M regulates the distribution and activity of various proteinases, growth factors, hormones, and cytokines (Krieger, 1994, Westwood et al., 2001). Recent evidence suggests that A2M acts as a tumor suppressor due to its ability to inactivate proteases that mediate tumor invasion, such as plasmin, urokinase plasminogen activator, and metalloproteinases (Sottrup-Jensen et al., 1989, Caceres et al., 2010).

We also found that A2M is downregulated in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), and that its expression is inversely correlated with tumor progression. Restoring A2M suppressed proliferation and invasion in paclitaxel-resistant lung cancer cells. Moreover, restoring A2M significantly reduced the expression of paclitaxel resistance inducers, including ABCB1, TMEM243, and ID1, thereby re-sensitizing resistant cells to paclitaxel. In conclusion, our findings suggest that A2M downregulation is a novel marker and mediator of paclitaxel resistance in lung cancer, and restoring A2M may re-sensitize cells to paclitaxel.